EP2129364B1 - Procédé de fabrication d'émulsions ophtalmiques huile-dans-eau - Google Patents

Procédé de fabrication d'émulsions ophtalmiques huile-dans-eau Download PDF

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Publication number
EP2129364B1
EP2129364B1 EP07858100.6A EP07858100A EP2129364B1 EP 2129364 B1 EP2129364 B1 EP 2129364B1 EP 07858100 A EP07858100 A EP 07858100A EP 2129364 B1 EP2129364 B1 EP 2129364B1
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Prior art keywords
oil
agents
process according
concentrate
emulsion
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German (de)
English (en)
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EP2129364A2 (fr
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Grégory LAMBERT
Frédéric Lallemand
Laura Rabinovich-Guilatt
Pascal Candillon
Julien Lafosse
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Santen SAS
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Santen SAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • Oil-in-water emulsions are widely used in ophthalmic products. Typical preparations of oil-in-water emulsions involve dissolving water-soluble components in an aqueous phase and dissolving oil-soluble components in an oil phase. The oil phase is then vigorously dispersed into the aqueous phase, for example, by mixing at several thousand revolutions per minute (r.p.m) for minutes to several hours. This process is called emulsification. Emulsification is an energy-consuming process, in which thermal and kinetic energies are invested in order to disperse the oil phase into numerous droplets of very small size but having a large total surface area.
  • Emulsions containing a high concentration of oil are way too uncomfortable to be suitable for ophthalmic uses. Therefore, the ophthalmic industry produces highly diluted oil-in-water emulsions.
  • the present invention relates to an improved strategy for the preparation of ready-to-dilute oil-in-water emulsions.
  • methods of preparation are provided that can be performed using equipments suitable for small to medium batch sizes. Compared to currently available processes, the methods provided herein exhibit satisfactory yields, require limited amounts of energy, and reasonable processing times.
  • the present invention pertains to the field of processes for manufacturing ophthalmic oil-in-water microemulsions or submicroemulsions.
  • Such processes generally comprise steps of: (1) manufacturing a pre-concentrate of an emulsion, and (2) diluting said pre-concentrate emulsion with a diluting aqueous solution to obtain the desired oil-in-water emulsion.
  • the present invention relates to processes for manufacturing ophthalmic oil-in-water emulsions comprising the steps of: (1) manufacturing a pre-concentrate of an emulsion, and (2) diluting said pre-concentrate emulsion with between 2 and 50 volumes of a diluting aqueous solution; wherein the pre-concentrate has a content in oil of between 6% and 50% v/v, preferably between 6% and 30%, more preferably between 10% and 20%.
  • the pre-concentrate is in the form of an emulsion, which may be a cationic emulsion, an anionic emulsion or a non-ionic emulsion.
  • a pre-concentrate of the present invention is a cationic emulsion pre-concentrate.
  • Processes according to the present invention aim at manufacturing thermodynamically stable oil-in-water microemulsion or submicroemulsions containing dispersed droplets, preferably having a mean size generally of more than about 10 nm and less than about 500 nm.
  • the mean size of the droplets may be of more than about 10 nm and less than about 300 nm, preferably less than about 200 nm.
  • microemulsions or submicroemulsions obtained using a process of the present invention are stable over periods of time in excess of about 12 months, preferably in excess of about 24 months, more preferably in excess of about 36 months.
  • the present invention relates to processes for manufacturing pre-concentrates of ophthalmic oil-in-water emulsions, preferably of ophthalmic oil-in-water microemulsions or submicroemulsions.
  • Such processes generally comprise a step of emulsifying an oil phase with an aqueous phase and at least one surface-active agent to obtain a pre-concentrate of an oil-in-water emulsion.
  • a pre-concentrate prepared by such a process generally has a content in oil that is higher than the content in oil of the final oil-in-water emulsion prepared by dilution of the pre-concentrate.
  • a pre-concentrate of the present invention is not suitable for direct administration to the eye of a patient, but becomes suitable for ophthalmic use after dilution.
  • a pre-concentrate of a desired oil-in-water emulsion is produced by emulsifying an oil phase comprising at least one oil, with an aqueous phase and at least one surfactant being tyloxapol; wherein the oil phase comprises at least one oil suitable for ophthalmic use selected from MCT and mineral oils; wherein the pre-concentrate obtained has a content in oil of between 6% and 50% v/v, preferably between 6% and 30%, more preferably between 10% and 20%; and wherein the step of emulsification is performed using colloid mills, rotor/stator homogenizers, high pressure homogenizers, sonicating homogenizers, high shear mixing apparatus or a combination thereof.
  • Oils that are suitable for ophthalmic use include, for example, castor oil, MCT, vegetal oils, mineral oils, and any combinations of these oils that are suitable for administration to the eye.
  • the average hydrophilic-lipophilic balance (HLB) of the surface-active agent(s) is advantageously substantially equal to the HLB or average HLB emulsion requirement of the oil or oils of the oil phase used in the preparation process.
  • the oil phase may comprise one or more pharmaceutically active substances, including prodrugs.
  • pharmaceutically active substances may be selected from the group consisting of antibiotics, antiviral agents, antifungals, intraocular pressure lowering agents, anti-inflammatory agents, steroids, anti-allergic compounds, anti-angiogenic compounds, biological agents, immunomodulating agents, cytostatics, antioxidants, UV-filter compounds, fatty acids, and the like.
  • An advantage of the processes provided by the present invention is that they allow production of large volumes of emulsions without having to scale-up the emulsifying step.
  • the present invention relates to processes for preparing a desired ophthalmic oil-in-water emulsion by diluting a pre-concentrate obtained as described above.
  • Such processes include diluting one volume of a pre-concentrate with 2 to 50 volumes of a diluting aqueous solution, such that the resulting ophthalmic oil-in-water emulsion has a content in oil of 5% v/v or less, preferably of 3% v/v or less, more preferably of 2% v/v or less, even more preferably of 1% v/v or less.
  • dilution is performed using 2 volumes of diluting aqueous solution for 1 volume of the pre-concentrate. More preferably, dilution is performed using 10 volumes of diluting aqueous solution for 1 volume of the pre-concentrate.
  • One advantage of such inventive processes is that oil-in-water emulsions obtained by dilution of pre-concentrates are formed with a lower energy input than that required in currently used processes.
  • the diluting aqueous solution comprises surfactants and/or additives, e.g., tonicity agents, viscosifying agents, buffering agents, preservatives, antioxidants, colorants or a micellar solution.
  • the diluting aqueous solution comprises benzalkonium chloride.
  • the diluting aqueous solution comprises one or more water-soluble therapeutic agent.
  • the present invention provides pre-concentrates of ophthalmic oil-in-water emulsions prepared by an inventive process.
  • a pre-concentrate is defined as an emulsion which may form a diluted emulsion by dilution which may form an emulsion (e.g., a microemulsion or submicroemulsion) by dilution in an aqueous medium, preferably on dilution of 1:1 to 1:50 (v/v), more preferably on dilution of 1:2 to 1:10 (v:v).
  • a pre-concentrate may be in a liquid form or in a gel form, or in any form suitable in view of its further dilution in an aqueous medium.
  • a pre-concentrate in the meaning of this invention is an emulsion comprising a content in oil higher than the content in oil of the final ophthalmic oil-in-water emulsion.
  • a pre-concentrate of an ophthalmic oil-in-water emulsion is not suitable for administration to a patient.
  • a pre-concentrate of the present invention comprises droplets having a size substantially equal to the size to the final ophthalmic oil-in-water emulsion droplet size, e.g., greater than about 10 nm and less than about 500 nm, less than about 300 nm, or preferably less than about 200 nm, preferably less than about 150 nm, typically less than about 100 nm.
  • a pre-concentrate of the present invention is stable for periods of time in excess of 24 hours, preferably in excess of 3 days, more preferably in excess of 7 days.
  • ophthalmic refers to a composition or emulsion intended to be administered to the eye of a subject and which presents a pharmaceutical effect.
  • subject and “individual” are used herein interchangeably. They refer to a human or another mammal (e.g., mouse, rat, rabbit, dog, cat, cattle, swine, sheep, horse or primate) that can be afflicted with or is susceptible to an eye disease or condition but may or may not have the disease or condition. In many embodiments, the subject is a human being.
  • mammal e.g., mouse, rat, rabbit, dog, cat, cattle, swine, sheep, horse or primate
  • the subject is a human being.
  • subject do not denote a particular age, and thus encompass adults, children, and newborns.
  • eye disease or condition refers to any of a wide variety of ocular conditions such as glaucoma, ocular inflammatory conditions such as keratitis, uveitis, ocular inflammation, post-surgical inflammation, allergy and dry eye syndrome ocular infections, ocular allergies, ocular infections, cancerous growth, neo vessel growth originating from the cornea, retinal oedema, macular oedema, diabetic retinopathy, retinopathy of prematurity, degenerative diseases of the retina (macular degeneration, retinal dystrophies), retinal diseases associated with glial proliferation, and the like.
  • ocular conditions such as glaucoma, ocular inflammatory conditions such as keratitis, uveitis, ocular inflammation, post-surgical inflammation, allergy and dry eye syndrome ocular infections, ocular allergies, ocular infections, cancerous growth, neo vessel growth originating from the cornea, retinal oedema, macular oedema,
  • treatment is used herein to characterize a method or process that is aimed at (1) delaying or preventing the onset of a disease or condition (in particular an eye disease or condition); (2) slowing down or stopping the progression, aggravation, or deterioration of the symptoms of the disease or condition; (3) bringing about amelioration of the symptoms of the disease or condition; or (4) curing the disease or condition.
  • a treatment may be administered prior to the onset of the disease or condition, for a prophylactic or preventive action.
  • a treatment may be administered after initiation of the disease or condition, for a therapeutic action.
  • a “pharmaceutical composition” is defined herein as comprising an effective amount of an inventive ophthalmic emulsion, and at least one pharmaceutically acceptable carrier or excipient.
  • the term "effective amount" refers to any amount of a compound, agent or composition that is sufficient to fulfill its intended purpose(s), e.g., a desired biological or medicinal response in a tissue, system or subject.
  • the purpose (s) may be: to slow down or stop the progression, aggravation, or deterioration of the symptoms of an eye disease or condition, to bring about amelioration of the symptoms of the disease or condition, and/or to cure the disease or condition. Determination of an effective amount is well within the ordinary skill in the art of pharmaceutical sciences and medicine, in that it may depend on various biological factors or individual variations and response to treatments.
  • pharmaceutically acceptable carrier or excipient refers to a carrier medium which does not interfere with the effectiveness of the biological activity of the active ingredient(s) and which is not excessively toxic to the host at a concentration at which it is administered.
  • the term includes solvents, dispersion media, antibacterial and antifungal agents, isotonic agents, adsorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art (see, for example, " Remington's Pharmaceutical Sciences", E.W. Martin, 18th Ed., 1990, Mack Publishing Co.: Easton, PA ).
  • therapeutic agent refers to a substance, molecule, compound, agent, factor or composition effective in the treatment of a disease or condition.
  • prodrug has herein its art understood meaning and refers to a pharmaceutically inactive compound that acts as a drug precursor which, following administration, is converted to and/or releases the pharmaceutically active drug. Conversion or release may occur via a chemical or physiological process (e.g., upon being brought to a physiological pH or through enzyme activity). Conversion or release may occur prior to, during, or following adsorption, or at a specific target site of the body.
  • Topical when used herein to characterize the delivery, administration or application of a composition of the present invention, is meant to specify that the composition is delivered, administered or applied directly to the site of interest (i.e., to the eye) for a localized effect. Topical administration may be effected without any significant absorption of components of the composition into the subject's blood stream (to avoid a systemic effect). Alternatively, topical administration may lead to at least some absorption of components of the composition into the subject's blood stream.
  • surface-active agent and “surfactant” are used herein interchangeably. They have their art understood meaning and refer to agents that lower the surface tension of a liquid, allowing easier spreading, and/or that lower the interfacial tension between two liquids.
  • Surfactants are generally organic compounds that are amphipathic (i.e., they contain both hydrophobic groups - called tails - and hydrophilic groups - called heads).
  • the present invention relates to processes for the preparation of oil-in-water emulsions that have the advantage of producing emulsions suitable for use in ophthalmic applications with satisfactory yields and in reasonable times, and that can be performed using equipment small to medium batch sizes.
  • Processes provided by the present invention generally comprise steps of: (1) manufacturing a pre-concentrate of an oil-in-water emulsion, and (2) diluting the pre-concentrate obtained in step (1) with a diluting aqueous phase to obtain an oil-in-water emulsion that can be used in ophthalmic applications.
  • Methods of manufacturing a pre-concentrate of an oil-in-water emulsion generally comprise a step of emulsifying an oil phase with an aqueous phase and at least one surface-active agent to obtain the pre-concentrate.
  • the oil phase comprises at least one oil suitable for ophthalmic use.
  • the methods of manufacturing a pre-concentrate of an oil-in-water emulsion according to the present invention comprise a step of emulsifying an oil phase with an aqueous phase and at least one surface-active agent being tyloxapol to obtain the pre-concentrate; wherein the oil phase comprises at least one oil suitable for ophthalmic use selected from MCT and mineral oils; wherein the pre-concentrate obtained has a content in oil of between 6% and 50% v/v, preferably between 6% and 30%, more preferably between 10% and 20%; and wherein emulsification is performed using colloid mills, rotor/stator homogenizers, high pressure homogenizers, sonicating homogenizers, high shear mixing apparatus or a combination thereof.
  • the step of emulsification may be performed by any suitable method including, but not limited to, methods using colloid mills, rotor/stator homogenizers, high pressure homogenizers, and sonicating homogenizers.
  • the emulsifying step requires an energy input lower than required in methods currently used for the preparation of a diluted ophthalmic oil-in-water emulsions.
  • the emulsifying step requires an energy input which is between about 2 and about 50 times lower than that required in currently available methods.
  • the energy input may be between about 2 and about 10 times lower, between about 5 and about 25 times lower, or between about 10 and about 50 times lower.
  • Oils suitable for ophthalmic use include, but are not limited to, castor oil, MCT, mineral oils, vegetal oils, and any combinations of these oils that are well tolerated at the eye level.
  • MCT refers to medium chain triglycerides. Medium chain triglycerides generally have a high solubility in water, are not significantly susceptible to oxidation, and are well suited for ophthalmic applications.
  • vegetal oils include, but are not limited to, cotton seed, ground nut, corn, germ, olive, palm, soybean, and sesame oils.
  • mineral oils include, but are not limited to, silicone and paraffin.
  • Methods of the present disclosure yield a pre-concentrate having a content in oil of between about 3% and about 50% v/v.
  • Methods of the present invention yield a pre-concentrate having a content in oil of between about 6% and about 50% v/v.
  • methods of the present invention yield a pre-concentrate having a content in oil of between about 6% and about 30% v/v.
  • methods of the present invention yield a pre-concentrate having a content in oil of between about 10% and about 20% v/v.
  • the step of emulsification which leads to the formation of a pre-concentrate is performed in the presence of an oil phase, an aqueous phase, and at least one surface-active agent (or surfactant).
  • surfactants suitable for use in processes of the present invention comprise tyloxapol and may optionally include further non-ionic surfactants, cationic surfactants, or anionic surfactants.
  • non-ionic surfactants examples include, but are not limited to, poloxamers, polysorbates (e.g., polysorbate 80), polyoxyethylene castor oil derivatives, derivatives of cremophors (e.g., cremophor EL, and cremophor RH), sorbitan esters, polyoxyl stearates, cremophors ( e.g., cremophor EL, and cremophor RH), and combinations thereof.
  • poloxamers e.g., polysorbate 80
  • polyoxyethylene castor oil derivatives derivatives of cremophors (e.g., cremophor EL, and cremophor RH)
  • cremophors e.g., cremophor EL, and cremophor RH
  • sorbitan esters e.g., polyoxyl stearates
  • cremophors e.g., cremophor EL, and cremophor RH
  • cationic surfactants that are suitable for use in the present invention include, but are not limited to, C 10 -C 24 primary alkylamines, tertiary aliphatic amines, quaternary ammonium compounds selected from the group comprising lauralkonium halide, cetrimide, hexadecyl-trimethylammonium halide, tetradecyltrimethyl-ammonium halide, dodecyltrimethyl-ammonium halide, cetrimonium halide, benzethonium halide, behenalkonium halide, cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide, benzododecinium halide, chlorallyl methenamine halide, myristalkonium halide, stearalkonium halide or a mixture of two or more thereof, halide being preferably chloride or bromide, cationic lipids,
  • the average hydrophilic-lipophilic balance (HLB) of the surface-active agent(s) is of the order of the required HLB or average HLB (RLHB) of the oil or oils of the oil phase used for the preparation of a pre-concentrate.
  • the RLHB value of the oil(s) of the oil phase and the HLB value of the surface-active agent (s) are substantially equal.
  • the term "hydrophilic-lipophilic balance or HLB” has its art understood meaning. When used in reference to a surfactant, it refers to a measure of the degree to which the surfactant is hydrophilic or lipophilic, determined by calculating values for the different regions of the molecule. The meaning of HLB value and RHLB value is discussed, for example, in " Encyclopedia of Emulsion Technology", P. Becher (Ed.), 1983, Marcel Dekker, 1: 217-220 .
  • the oil phase used in the preparation of a pre-concentrate according to the present invention further comprises at least one pharmaceutically active substance or a prodrug.
  • pharmaceutically active substances or prodrugs are soluble in the oil phase.
  • antibiotics e.g., aminoglycosides, carbacephem, carbapenems, macrolides, cephalosporins, glycopeptides, penicillins, polypeptides, quinolones, sulfonamides, tetracyclines and the like
  • antiviral agents e.g., cidofovir, ganciclovir, valaciclovir or acyclovir
  • antifungals e.g., polyene antibiotics, imidazole and triazole, allylamines
  • intraocular pressure lowering agents e.g., alpha-adrenergic agonists, beta-adrenergic blockers, carbonic anhydrase inhibitors, cannabinoids, derivatives and prodrugs
  • anti-inflammatory agents including non-steroidal anti-inflammatory agents (e.g., COX-2 inhibitors,
  • the pharmaceutically active substance is a non-steroidal anti-inflammatory agent, e.g., flubiprofen.
  • anti-glaucomateaous active substances that can be selected among beta-blockers (e.g., levobunolol, befundol, metipranolol, forskolin, cartrolol, timolol); inhibitors of carbonic anhydrase (e.g., brinzolamide, dorzolamide, acetazolamide, methazolamide, dichloro-phenamide); sympathomimetics (e.g., brimonidine, apraclonidine, dipivefrine, epinephrine); parasympathomimetics ( e.g., pilocarpine); or cholinesterase inhibitors (e.g., physostigmine, echothiophate and/or their derivatives and/or pharmaceutically acceptable salts thereof).
  • beta-blockers e.g., levobunolol, befundol, metipranolol, forskolin, cartrolol, timol
  • pharmaceutically active substances or prodrugs that can be used in the practice of the present invention include, but are not limited to, prostaglandins, preferably prostaglandin F 2 ⁇ analogs such as, for example, latanoprost, unoprostone isopropyl, travoprost, bimatoprost, tafluprost, 8-isoprostaglandin E2, or any combination thereof.
  • the pharmaceutically active substance may be latanoprost.
  • corticosteroids include, but are not limited to, betamethasone, budenoside, cortisone, dexamethasone, hydrocortisone, methylprednisoline, prednisolone, prednisone, and triamcinolone.
  • the oil phase used to prepare a pre-concentrate according to the present invention comprises a prodrug of a corticosteroid, for example a prodrug of dexamethasone, e.g., dexamethasone palmitate.
  • the amount of pharmaceutically active substance(s) included in the oil phase is generally such that the amount of active substance(s) in the final oil-in-water ophthalmic emulsion is comprised between about 0.001% and 3%.
  • pre-concentrates prepared according to a process of the present invention comprise droplets having a mean size greater than about 10 nm and less than about 500 nm, preferably less than about 300 nm or less than about 200 nm.
  • the mean size of droplets in an inventive pre-concentrate is substantially the same as the mean size of droplets in the ophthalmic oil-in-water emulsion prepared therefrom.
  • pre-concentrates prepared according to a process of the present invention are stable over periods of time in excess of 24 hours, preferably in excess of 3 days, more preferably in excess of 7 days.
  • Pre-concentrates prepared according to processes of the present invention may be under any form that is suitable for its further dilution in an aqueous medium.
  • a pre-concentrate of the invention is in a liquid form.
  • a pre-concentrate is in a gel form.
  • a pre-concentrate of the invention is in the form of an emulsion, which may be a cationic emulsion (i.e., a composition comprising colloid particles having a positive zeta potential), an anionic emulsion (i.e., a composition comprising colloid particles having a negative zeta potential), or a non-ionic emulsion (i.e., a composition comprising colloid particles having a zeta potential null).
  • the zeta potential is a measure of the magnitude of repulsion or attraction between particles.
  • the zeta potential is not measurable directly but it can be calculated using theoretical models and an experimentally-determined electrophoretic mobility or dynamic electrophoretic mobility.
  • electrophoretic mobility can be determined using micro-electrophoresis or electrophoretic light scattering.
  • a pre-concentrate is preferably in the form of a cationic emulsion.
  • pre-concentrates produced by processes of the present invention are not suitable for administration to the eye of a subject, but becomes suitable for ophthalmic use after dilution with an aqueous medium.
  • the present invention also provides processes for the manufacture of ophthalmic oil-in-water emulsions.
  • Such processes generally comprise steps of: manufacturing a pre-concentrate as described above; and diluting one volume of the pre-concentrate with between 2 and 50 volumes of a diluting aqueous solution, for example between 2 and 25 volumes, or between 2 and 10 volumes.
  • pre-concentrates used in such processes have a content in oil of between about 6% and about 50% v/v, e.g., between about 6% and about 30% v/v or between about 10% and about 20% v/v; and comprise at least one oil that is suitable for use in ophthalmic applications.
  • the diluting aqueous phase comprise one or more additives selected from the group consisting of emulsifying agents, suspending agents, dispersing or wetting agents, tonicity agents, viscosifying agents, buffering agents, preservatives, chelating agents, anti-foaming agents, antioxidants, colorants, and any combinations thereof.
  • emulsifying agents are naturally occurring gums, naturally occurring phosphatides (e.g., soybean lecithin, sorbitan mono-oleate derivatives), sorbitan esters, mono glycerides, fatty alcohols ( e.g., cetyl alcohol, oleyl alcohol), and fatty acid esters ( e.g., triglycerides of fatty acids, sodium cetostearyl sulfate).
  • Emulsifying agents may be present at a concentration between about 0.01% and about 1% w/w. In this section, percentages are given in weight/weight (w/w) of the final emulsion.
  • buffering agents examples include citric acid, acetic acid, lactic acid, hydrogenophosphoric acid, diethylamine, sodium hydroxide and tromethane (i.e., tris-(hydroxymethyl)aminomethane hydrochloride). Buffering agents may be present at a concentration between about 5 mM and about 100 m.
  • Suitable suspending agents are, for example, naturally occurring gums (e.g., acacia, arabic, xanthan, and tragacanth gum), celluloses (e.g., carboxymethyl-, hydroxyethyl-, hydroxypropyl-, and hydroxypropylmethyl-cellulose), alginates and chitosans. Suspending agents may be present at a concentration between about 0.1% to about 15% w/w.
  • dispersing or wetting agents are naturally occurring phosphatides (e.g., lecithin or soybean lecithin), condensation products of ethylene oxide with fatty acids or with long chain aliphatic alcohols (e.g., polyoxyethylene stearate, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate). Dispersing or wetting agents may be present at a concentration between about 0.001% to about 5% w/w.
  • tonicity agents include, but are not limited to, NaCl, glycerol and mannitol. Tonicity agents may be present at a concentration between about 0.1% to about 5% w/w.
  • Preservatives may be added to a composition of the invention to prevent microbial contamination that can affect the stability of the formulation and/or cause infection in the patient.
  • Suitable examples of preservatives include chlorexidine, polyoxyethylen biguenide, parabens (such as methyl, ethyl, propyl, p -hydroxybenzoate, butyl, isobutyl, and isopropylparaben), potassium sorbate, sorbic acid, benzoic acid, methyl benzoate, phenoxyethanol, bronopol, bronidox, MDM hydantoin, iodopropynyl butylcarbamate, benzalconium chloride, cetrimide, and benzylalcohol.
  • Preservatives may be present at a concentration between about 0.0001% and about 0.02% w/w.
  • chelating agents examples include sodium EDTA and citric acid. Chelating agents may be present at a concentration between about 0.001% and about 0.1% w/w.
  • Anti-foaming agents usually facilitate manufacture of compositions, they dissipate foam by destabilizing the air-liquid interface and allow liquid to drain away from air pockets.
  • Examples of anti-foaming agents include simethicone, dimethicone, ethanol, and ether. Anti-foaming agents may be present at a concentration between about 0.1% and about 5% w/w.
  • gel bases or viscosity-increasing agents are liquid paraffin, polyethylene, fatty oils, colloidal silica or aluminum, glycerol, propylene glycol, propylene carbonate, carboxyvinyl polymers, magnesium-aluminum silicates, hydrophilic polymers (such as, for example, starch or cellulose derivatives), water-swellable hydrocolloids, carragenans, hyaluronates, alginates, and acrylates.
  • Gel bases and viscosity-increasing agents may be present at a concentration between about 0.5% and about 10% w/w.
  • a diluting aqueous solution used in a process of the present invention alternatively or additionally, comprises benzalkonium chloride.
  • Benzalkonium chloride a nitrogenous cationic surface-acting agent belonging to the family of quaternary ammonium compounds, is the most commonly used preservative in ophthalmology.
  • Benzalkonium chloride also has cationic agent properties, and is used as cationic agents for emulsions, especially ophthalmic emulsions.
  • Benzalkonium chloride is a mixture of n-alkyl dimethyl benzyl ammonium chlorides of various alkyl chain lengths.
  • FeF Chemicals A/S (Denmark) supplies, under reference 8100301U (BAK USP/NF), a mixture of three alkyl dimethyl benzyl ammonium chlorides including : (1) 60-70% of C 12 -alkyl dimethyl benzyl ammonium chloride (2) 30-40% of C 14 -alkyl dimethyl benzyl ammonium chloride, and less than 5% of C 16 -alkyl dimethyl benzyl ammonium chloride.
  • BAK may be present at a concentration between about 0.005% and about 0.02% w/w.
  • the diluting aqueous phase comprises, alternatively or additionally, at least one water-soluble therapeutic agent.
  • Suitable water-soluble therapeutic agents may be found in a wide variety of classes of drugs including, but not limited to, analgesics, anesthetics, relaxants, hormones, anti-inflammatory agents, vitamins, minerals, anti-angiogenic agents, wound healing agents, cytokines, growth factors, anti-histaminic agents, anti-bacterial agents, anti-viral agents, antibiotics, antipruritic agents, antipyretic agents, and the like.
  • Ophthalmic oil-in-water emulsions prepared according to processes provided herein generally have a content in oil of 5% v/v or less, preferably of 3% v/v or less, more preferably of 2% v/v or les, even more preferably of 1% v/v or less. They generally contain droplets having a mean size greater than about 10 nm and less than about 500 nm, preferably less than about 300 nm or less than about 200 nm.
  • the mean size of droplets in an inventive oil-in-water emulsion is substantially the same as the mean size of droplets in the pre-concentration from which it is prepared by dilution.
  • an inventive oil-in-water emulsion is stable over a period of time greater than about 12 months, preferably greater than about 24 months, or more preferably greater than about 36 months.
  • Ophthalmic oil-in-water emulsions disclosed herein may be administered per se or in the form of a pharmaceutical composition. Accordingly, the present disclosure provides pharmaceutical compositions comprising an effective amount of an oil-in-water emulsion described herein and at least one pharmaceutically acceptable carrier, vehicle or excipient. As will be recognized by one skilled in the art, pharmaceutically acceptable carriers or excipients may be included in the diluting aqueous phase used in the preparation of the emulsion from an inventive pre-concentrate.
  • compositions of the present disclosure may be in the form of liquid or semi-solid dosage preparations.
  • they may be formulated as emulsions, lotions, liniments, jellies, ointments, creams, pastes, gels, hydrogels, aerosols, sprays, foams, and the like.
  • compositions may be prepared according to general pharmaceutical practice (see, for example, " Remington's Pharmaceutical Sciences”, E.W. Martin, 18th Ed., 1990, Mack Publishing Co.: Easton, PA and " Encyclopedia of Pharmaceutical Technology", 1988, J. Swarbrick, and J.C. Boylan (Eds.), Marcel Dekker, Inc: New York ).
  • compositions of the present disclosure can be routinely selected for a particular use by those skilled in the art.
  • Such carriers, vehicles and excipients include, but are not limited to, solvents, buffering agents, inert diluents, suspending agents, dispersing agents or wetting agents, preservatives, stabilizers, chelating agents, emulsifying agents, anti-foaming agents, gel-forming agents, humectants, and the like.
  • Excipient characteristics that are considered include, but are not limited to, the biocompatibility and biodegradability at the site of administration, compatibility with pharmaceutically active substances present, and processing conditions, such as temperature, pressure, and the like.
  • compositions are formulated to provide a local controlled release of one or more components of the composition.
  • Any pharmaceutically acceptable carrier, vehicle or excipient suitable for administration to the eye may be employed.
  • slow release formulation include polymer formulations (such as vesicles or liposomes) and microparticles (such as microspheres or microcapsules).
  • biodegradable materials may be used to provide controlled release of one or more components of compositions of the present disclosure.
  • the controlled release material should be biocompatible and be degraded, dissolved or absorbed in situ in a safe and pharmaceutically acceptable manner so that the material is removed from the site of administration by natural tissue processes and in a suitable amount of time.
  • the controlled release carrier should not cause any unwanted local tissue reaction or induce systemic or local toxicity.
  • Suitable controlled release biodegradable polymers for use in the formulation of compositions of the disclosure may comprise polylactides, polyglycolides, poly(lactide-co-glycolides), polyanhydrides, polyorthoesters, polycaprolactones, polysaccharides, polyphosphazenes, proteinaceous polymers and their soluble derivatives (such as gelation biodegradable synthetic polypeptides, alkylated collagen, and alkylated elastin), soluble derivatives of polysaccharides, polypeptides, polyesters, and polyorthoesters.
  • polylactides polyglycolides, poly(lactide-co-glycolides), polyanhydrides, polyorthoesters, polycaprolactones, polysaccharides, polyphosphazenes, proteinaceous polymers and their soluble derivatives (such as gelation biodegradable synthetic polypeptides, alkylated collagen, and alkylated elastin), soluble derivatives of
  • the pharmacokinetic release profile of these formulations may be first order, zero order, bi- or multi-phasic, to provide the desired therapeutic effect over the desired period of time.
  • a desired release profile can be achieved by using a mixture of polymers having different release rates and/or different percent loadings of a pharmaceutically active substance. Methods for the manufacture of liposomes, microspheres and microcapsules are well known in the art.
  • compositions of the present disclosure may be formulated in dosage unit form for ease of administration and uniformity of dosage.
  • unit dosage form refers to a physically discrete amount of an emulsion to treat a patient. It will be understood, however, that the total daily dose of compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • compositions of the present disclosure are combined with, coated on, or incorporated within a device that can be applied to the eye, e.g., an ocular lens.
  • a pre-concentrate and/or the resulting oil-in-water emulsion may be sterilized using any suitable method including, but not limited to, by heat, such as by autoclaving, or by filtering or filtration, or by irradiation, or by gas sterilization.
  • the pre-concentrate is prepared under aseptic conditions.
  • the final oil-in-water emulsion is sterilized following the dilution step.
  • dilution is performed under aseptic conditions.
  • a pharmaceutical composition to be administered to the eye of a subject is sterile.
  • the present disclosure relates to methods for the treatment of eye diseases or conditions.
  • Such methods generally comprise a step of administering to a subject in need thereof, an effective amount of an ophthalmic oil-in-water emulsion obtained by a process disclosed herein.
  • Administration may be by any suitable method, including topical administration, intraocular administration, and periocular administration.
  • Eye diseases or conditions that can be treated using emulsions and methods of the present disclosure may be any of a wide variety of ocular conditions such as glaucoma, ocular inflammatory conditions such as keratitis, uveitis, intra-ocular inflammation, post-surgery inflammation, allergy and dry-eye syndrome ocular infections, ocular allergies, ocular infections, cancerous growth, neo vessel growth originating from the cornea, retinal oedema, macular oedema, diabetic retinopathy, retinopathy of prematurity, degenerative diseases of the retina (macular degeneration, retinal dystrophies), and retinal diseases associated with glial proliferation.
  • ocular conditions such as glaucoma, ocular inflammatory conditions such as keratitis, uveitis, intra-ocular inflammation, post-surgery inflammation, allergy and dry-eye syndrome ocular infections, ocular allergies, ocular infections, cancerous growth, neo vessel growth originating
  • a treatment according to the present disclosure may consist of a single dose or a plurality of doses over a period of time. Administration may be one or multiple times daily, weekly (or at some other multiple day interval) or on an intermittent schedule.
  • Final dosage regimen will be determined by the attending physician, considering various factors which modify the action of the drug, e.g., the drug's specific activity, the severity of the disease or condition and the responsiveness of the patient, the age, condition, body weight, sex and diet of the patient, the severity of any present infection, time of administration, the use (or not) of concomitant therapies, and other clinical factors.
  • compositions of the present disclosure can be employed alone or in combination with additional therapies.
  • a treatment according to the present invention can be administered concurrently with, prior to, and/or following one or more desired therapeutics or medical procedures.
  • the particular combination of therapies (therapeutics or procedures) to employ in such combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
  • a pharmaceutical composition of the present disclosure may be administered to a subject following eye surgery.
  • eye surgery procedures include, but are not limited to, laser surgery; cataract surgery; glaucoma surgery (e.g., canaloplasty), refractive surgery (e.g., keratomilleusis, automated lamellar keratoplasty, Laser assisted in situ keratomileusis or LASIK, photorefractive keratectomy, laser thermal keratoplasty, conductive keratoplasty, and astigmatic keratotomy); corneal surgery ( e.g., corneal transplant surgery, penetrating keratoplasty, and phototherapeutic keratectomy); vitréo-retinal surgery (e.g., vitrectomy, retinal detachment repair, and macular hole repair); eye muscle surgery; oculoplastic surgery; eyelid surgery; orbital surgery; and other ophthalmologic surgery procedures.
  • laser surgery e.g., cataract surgery
  • glaucoma surgery e.g., canaloplasty
  • a pharmaceutical pack or kit comprises one or more containers (e.g., vials, ampoules, test tubes, flasks, bottles, or pre-filled syringes) containing one or more ingredients of a disclosed composition, allowing administration of the composition to a subject.
  • containers e.g., vials, ampoules, test tubes, flasks, bottles, or pre-filled syringes
  • Such containers may be made of glass, plastic materials, resins, and the like. They may be transparent or, alternatively, they may be colored or opaque to prevent or reduce the risk that active ingredients be directly exposed to light.
  • a container is in a form that allows for administration of a controlled volume (e.g., a drop) of a disclosed composition.
  • a container comprises a system (e.g., a dropper) allowing administration of a controlled volume of a disclosedcomposition.
  • Different ingredients of a pharmaceutical pack or kit may be supplied in a liquid form or in a solid form (e.g., lyophilized). Each ingredient will generally be suitable as aliquoted in its respective container or provided in a concentrated form. Pharmaceutical packs or kits may include media for the reconstitution of lyophilized ingredients. Individual containers of a kit will preferably be maintained in close confinement for commercial sale.
  • a pharmaceutical pack or kit includes one or more additional approved therapeutic agents as described above.
  • Optionally associated with such container(s) can be a notice or package insert in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • the notice or package insert may contain instructions for use of a pharmaceutical composition according to methods disclosed herein.
  • An identifier e.g., a bar code, radio frequency, ID tags, etc.
  • the identifier can be used, for example, to uniquely identify the kit for purposes of quality control, inventory control, tracking movement between workstations, etc.
  • Example 1 Preparation of One Batch of 100 kg of an Emulsion Comprising Cyclosporine A
  • FIG. 1 presents a scheme of the compounding process used in the preparation.
  • each phase was prepared separately including the API in the oily phase.
  • the aqueous phase and oil phase obtained in steps 1 and 2 were then then diluted to get a premix (w/w) in step 3.
  • the resulting premix was submitted to a high-shear mixing for about 30 minutes to 1 hour (Step 4), and then homogenized under high pressure for about 5 hours (Step 5).
  • a second dilution was then performed (Step 6 and 7) in a ratio of 1 w premix/6 w aqueous phase 2, to obtain the final emulsion, which was then sterilized by heating (Step 8).
  • Example 2 Preparation of one Batch of 500 kg of an Emulsion that does not comprise API
  • FIG. 2 presents a scheme of the compounding process used in the preparation.
  • steps 1, 2 and 6 each phase was prepared separately.
  • the aqueous phase and oil phase obtained in steps 1 and 2 were then diluted to get a premix (w/w) in step 3.
  • the resulting premix was submitted to a high-shear mixing for about 1 hour (Step 4), and then homogenized under high pressure for about 8 hours (Step 5).
  • a second dilution was then performed (Step 6 and 7) in a ratio of 1 w premix/10 w aqueous phase 2, to obtain the final emulsion, which was then sterilized by heating (Step 8).
  • Example 3 Preparation of one Batch of 100 kg of an Emulsion Comprising Naphazolin
  • FIG. 3 presents a scheme of the compounding process used in the preparation.
  • each phase was prepared separately.
  • the API was included in the aqueous phase.
  • the aqueous phase and oil phase obtained in steps 1 and 2 were then diluted to get a premix (w/w) in step 3.
  • the resulting premix was submitted to a high-shear mixing for about 30 minutes (Step 4), and then homogenized under high pressure for about 5 hours (Step 5).
  • a second dilution was then performed (Step 6 and 7) in a ratio of 1 w premix/25 w aqueous phase 2, to obtain the final emulsion, which was then sterilized by heating (Step 8) .

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Claims (20)

  1. Procédé de fabrication d'un préconcentré d'une émulsion ophtalmique huile-dans-eau, ledit procédé comprenant une étape de :
    émulsionner une phase huileuse avec une phase aqueuse et au moins un agent de surface étant le tyloxapol, pour obtenir le préconcentré,
    dans laquelle la phase huileuse comprend au moins une huile adaptée à une utilisation ophtalmique choisie parmi les triglycérides à chaîne moyenne (MCT) et les huiles minérales,
    dans lequel le préconcentré obtenu a une teneur en huile comprise entre 6% et 50% v/v, de préférence entre 6% et 30%, plus préférentiellement entre 10% et 20%, et
    dans lequel l'émulsification est effectuée en utilisant des broyeurs à colloïdes, des homogénéisateurs à rotor/stator, des homogénéisateurs à haute pression, des homogénéisateurs à ultrasons, des mélangeurs à cisaillement élevé ou une combinaison de ceux-ci.
  2. Procédé selon la revendication 1, dans lequel la phase huileuse comprend en outre une huile appropriée pour une utilisation ophtalmique choisie dans le groupe constitué par l'huile de ricin, les huiles végétales, et toute combinaison de celles-ci.
  3. Procédé selon la revendication 1 ou 2, dans lequel la phase huileuse comprend en outre au moins une substance pharmaceutiquement active.
  4. Procédé selon la revendication 3, dans lequel la substance pharmaceutiquement active est choisie dans le groupe consistant en antibiotiques, agents antiviraux, antifongiques, agents abaissant la pression intraoculaire, agents anti-inflammatoires, stéroïdes, composés anti-allergiques, composés anti-angiogéniques, anticorps et leurs fragments, oligoaptamères, aptamères et fragments de gènes, oligonucléotides, plasmides, ribozymes, petit ARN d'interférence, fragments d'acide nucléique, peptides et séquences antisens, facteurs de croissance, agents immunomodulateurs, médicaments agissant sur les immunophilines, interférons, opioïdes, cytostatiques, antioxydants, composés filtrants les UV, agents anti-rougeurs, acides gras oméga-3, promédicaments de ceux-ci, et toute combinaison de ceux-ci.
  5. Procédé selon la revendication 3, dans lequel la substance pharmaceutiquement active est choisie dans le groupe consistant en cyclosporine A, latanoprost, palmitate de dexaméthasone, et flurbiprofène.
  6. Procédé selon l'une quelconque des revendications 1 à 5, dans lequel le préconcentré comprend des gouttelettes ayant une taille moyenne supérieure à environ 10 nm et inférieure à environ 500 nm, de préférence supérieure à environ 10 nm et inférieure à environ 300 nm, de manière préférée entre toutes plus d'environ 10 nm et moins d'environ 200 nm.
  7. Procédé selon l'une quelconque des revendications 1 à 6, dans lequel le préconcentré est stable sur une période de temps dépassant au moins 24 heures, de préférence au moins 3 jours, de manière préférée entre toutes au moins 7 jours.
  8. Procédé selon l'une quelconque des revendications 1 à 7, dans lequel le préconcentré se présente sous la forme d'une émulsion cationique, d'une émulsion anionique ou d'une émulsion non-ionique.
  9. Procédé selon la revendication 8, dans lequel le préconcentré se présente sous la forme d'une émulsion cationique.
  10. Procédé de fabrication d'une émulsion ophtalmique huile-dans-eau, ledit procédé comprenant les étapes de :
    fabrication d'un préconcentré d'une émulsion ophtalmique huile-dans-eau selon le procédé selon l'une quelconque des revendications 1 à 9,
    dilution d'un volume du préconcentré avec entre 2 et 50 volumes d'une solution aqueuse de dilution,
    dans lequel le préconcentré a une teneur en huile comprise entre 6% et 50% v/v, de préférence entre 6% et 30%, plus préférentiellement entre 10% et 20%.
  11. Procédé selon la revendication 10, dans lequel la solution aqueuse de dilution comprend un additif choisi dans le groupe comprenant les agents de tonicité, les agents viscosifiants, les agents tampons, les conservateurs, les antioxydants, les colorants, les solutions micellaires, et leurs combinaisons.
  12. Procédé selon la revendication 10 ou 11, dans lequel la solution aqueuse de dilution comprend du chlorure de benzalkonium.
  13. Procédé selon l'une quelconque des revendications 10 à 12, dans lequel la solution aqueuse de dilution comprend au moins un agent thérapeutique hydrosoluble.
  14. Procédé selon la revendication 13, dans lequel l'agent thérapeutique hydrosoluble est un membre hydrosoluble du groupe consistant en analgésiques, anesthésiques, relaxants, hormones, agents anti-inflammatoires, vitamines, minéraux, agents anti-angiogéniques, agents de cicatrisation, cytokines, facteurs de croissance, agents antihistaminiques, agents antibactériens, agents antiviraux, antibiotiques, agents antiprurigineux, agents antipyrétiques et similaires.
  15. Procédé selon l'une quelconque des revendications 10 à 14, dans lequel la fabrication d'un préconcentré d'une émulsion ophtalmique huile-dans-eau est effectuée en utilisant un procédé selon l'une quelconque des revendications 1 à 9.
  16. Procédé selon l'une quelconque des revendications 1 à 15, dans lequel l'émulsion huile-dans-eau comprend des gouttelettes ayant une taille moyenne supérieure à environ 10 nm et inférieure à environ 500 nm, de préférence supérieure à environ 10 nm et inférieure à environ 300 nm, plus préférentiellement supérieure à environ 10 nm et inférieure à environ 200 nm.
  17. Procédé selon l'une quelconque des revendications 1 à 16, dans lequel l'émulsion huile-dans-eau est stable pendant une durée dépassant au moins 12 mois, de préférence au moins 24 mois, plus préférentiellement au moins 36 mois.
  18. Procédé selon l'une quelconque des revendications 1 à 17, dans lequel l'émulsion huile-dans-eau se présente sous la forme d'une émulsion cationique, d'une émulsion anionique ou d'une émulsion non-ionique.
  19. Procédé selon l'une quelconque des revendications 1 à 18, dans lequel l'émulsion huile-dans-eau se présente sous la forme d'une émulsion cationique.
  20. Préconcentré d'une émulsion ophtalmique huile-dans-eau obtenu par un procédé selon l'une quelconque des revendications 1 à 9.
EP07858100.6A 2006-12-21 2007-12-21 Procédé de fabrication d'émulsions ophtalmiques huile-dans-eau Active EP2129364B1 (fr)

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CA2672973A1 (fr) 2008-06-26
WO2008074885A2 (fr) 2008-06-26
JP5850602B2 (ja) 2016-02-03
US20080181867A1 (en) 2008-07-31
JP2011506266A (ja) 2011-03-03
ES2796116T3 (es) 2020-11-25
IL199458A (en) 2015-04-30
CA2672973C (fr) 2016-03-08
WO2008074885A3 (fr) 2008-10-09
EP2129364A2 (fr) 2009-12-09
US9364461B2 (en) 2016-06-14

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